Intrathecal methotrexate is widely used for the treatment of brain tumors, meningeal leukemia, lymphomatous meningitis and other neoplasms metastatic to the central nervous system. Unfortunately, therapeutic and toxic effects of this therapeutic modality vary markedly from patient to patient, despite constancy of dosage and treatment interval in all patients. Pharmacokinetic factors may help explain the observed interpatient variability in tumor response and drug toxicity, and potentially can be utilized to improve intrathecal chemotherapy in the individual patient. This project proposes to characterize plasma and cerebrospinal-fluid antifolate concentrations in patients receiving intrathecal methotrexate. Correlations of antifolate concentrations with remission durations and with neurologic and systemic toxicities will be attempted. Factors capable of influencing the pharmacokinetics, such as brain volume, body surface area, age and the presence of malignant cells in the central nervous system, will also be examined. The overall objectives are to establish pharmacologic criteria for safer, more effective dosage regimens for intrathecal methotrexate therapy, and to develop pharmacokinetic concepts applicable to intrathecal chemotherapeutic agents in general.